L.M. Hertan

Thioredoxin Reductase-1 Mediates Curcumin-Induced Radiosensitization of Squamous Carcinoma Cells

Curcumin, a plant polyphenol, is a widely studied chemopreventive agent with demonstrated antitumor activities in preclinical studies and low toxicity profiles in multiple clinical trials against human malignancies. We previously showed that curcumin radiosensitizes cervical tumor cells without increasing the cytotoxic effects of radiation on normal human fibroblasts. Here we report that an inhibitory activity of curcumin on the antioxidant enzyme thioredoxin reductase-1 (TxnRd1) is required for curcumin-mediated radiosensitization of squamous carcinoma cells. Stable knockdown of TxnRd1 in both HeLa and FaDu cells nearly abolished curcumin-mediated radiosensitization. TxnRd1 knockdown cells showed decreased radiation-induced reactive oxygen species and sustained extracellular signal-regulated kinase 1/2 activation, which we previously showed was required for curcumin-mediated radiosensitization. Conversely, overexpressing catalytically active TxnRd1 in HEK293 cells, with low basal levels of TxnRd1, increased their sensitivity to curcumin alone and to the combination of curcumin and ionizing radiation. These results show the critical role of TxnRd1 in curcumin-mediated radiosensitization and suggest that TxnRd1 levels in tumors could have clinical value as a predictor of response to curcumin and radiotherapy.

Effect of Body Mass Index on Magnitude of Setup Errors in Patients Treated With Adjuvant Radiotherapy for Endometrial Cancer With Daily Image Guidance

PURPOSE To determine the impact of body mass index (BMI) on daily setup variations and frequency of imaging necessary for patients with endometrial cancer treated with adjuvant intensity-modulated radiotherapy (IMRT) with daily image guidance. METHODS AND MATERIALS The daily shifts from a total of 782 orthogonal kilovoltage images from 30 patients who received pelvic IMRT between July 2008 and August 2010 were analyzed. The BMI, mean daily shifts, and random and systematic errors in each translational and rotational direction were calculated for each patient. Margin recipes were generated based on BMI. Linear regression and spearman rank correlation analysis were performed. To simulate a less-than-daily IGRT protocol, the average shift of the first five fractions was applied to subsequent setups without IGRT for assessing the impact on setup error and margin requirements. RESULTS Median BMI was 32.9 (range, 23-62). Of the 30 patients, 16.7% (n = 5) were normal weight (BMI <25); 23.3% (n = 7) were overweight (BMI ≥ 25 to <30); 26.7% (n = 8) were mildly obese (BMI ≥ 30 to <35); and 33.3% (n = 10) were moderately to severely obese (BMI ≥ 35). On linear regression, mean absolute vertical, longitudinal, and lateral shifts positively correlated with BMI (p = 0.0127, p = 0.0037, and p < 0.0001, respectively). Systematic errors in the longitudinal and vertical direction were found to be positively correlated with BMI category (p < 0.0001 for both). IGRT for the first five fractions, followed by correction of the mean error for all subsequent fractions, led to a substantial reduction in setup error and resultant margin requirement overall compared with no IGRT. CONCLUSIONS Daily shifts, systematic errors, and margin requirements were greatest in obese patients. For women who are normal or overweight, a planning target margin margin of 7 to 10 mm may be sufficient without IGRT, but for patients who are moderately or severely obese, this is insufficient.

The chemopreventive and clinically used agent curcumin sensitizes HPV- but not HPV+ HNSCC to ionizing radiation, in vitro and in a mouse orthotopic model

Radiation therapy (RT) plays a critical role in the local-regional control of head and neck squamous cell carcinoma (HNSCC). However, the efficacy of RT in treating HNSCC is limited by severe normal tissue toxicity, predominantly mucositis. One pharmacological approach for increasing the clinical response to RT is the use of radiation response modifiers that preferentially sensitize tumor cells. Previously we demonstrated that curcumin, a natural plant polyphenol, increased the radiation sensitivity of HNSCC cells and that the observed sensitization was dependent on curcumin-mediated inhibition of thioredoxin reductase 1 (TxnRd1) a key cytosolic regulator of redox-dependent signaling. Here, we examined curcumin-induced radiation sensitization in HNSCC cell lines with differing HPV status and expressing different levels of TxnRd1, in vitro. The intrinsic radiation resistance of the HPV- cell lines was significantly higher than the HPV+ cell lines used in our study. Notably, all of the HPV- cell lines expressed high levels of TxnRd1 and exhibited higher intrinsic resistance to RT. While curcumin was effective at increasing the radiation response of the resistant HPV- cell lines it had no effect on the HPV+ cells. Based on these findings we employed an orthotopic, HPV- HNSCC tumor model in athymic nude mice to examine the effect of combining curcumin with fractionated RT, in vivo. The combination of curcumin feeding and fractionated RT had a significant effect on tumor doubling time and overall animal survival. We therefore propose that curcumin and RT should be considered as a first line treatment of HPV- HNSCC.

Indian gold treating cancer in the age of nano.

Commentary to: A polymeric nanoparticle formulation of curcumin inhibits growth, clonogenicity and stem-like fraction in malignant brain tumors Kah Jing Lim, Savita Bisht, Eli E. Bar, Anirban Maitra and Charles G. Eberhart

Palliative radiotherapy: current status and future directions.

For nearly 100 years, palliative radiotherapy has been a time-efficient, effective treatment for patients with metastatic or advanced cancer in any area where local tumors are causing symptoms. Short courses including a single fraction of radiotherapy may be effective for symptom relief with minimal side effects and maximization of convenience for patient and family. With recent advances in imaging, surgery, and other local therapies as well as systemic cancer therapies, palliative radiotherapy has been used frequently in patients who may not yet have symptoms of advanced or metastatic cancer. In this setting, more prolonged radiotherapy courses and advanced radiotherapy techniques including intensity-modulated radiotherapy (IMRT) or stereotactic radiotherapy (SRT) may be useful in obtaining local control and durable palliative responses. This review will explore the use of radiotherapy across the spectrum of patients with advanced and metastatic cancer and delineate an updated, rational approach for the use of palliative radiotherapy that incorporates symptoms, prognosis, and other factors into the delivery of palliative radiotherapy.

Special topics in immunotherapy and radiation therapy: Reirradiation and palliation

Immunotherapy has revolutionized the treatment of non-small cell lung cancer (NSCLC). However, thus far, its use has only been established in patients with advanced disease either as first-line therapy in selected patients or following chemotherapy. What is not yet known is how best to incorporate radiation with immunotherapy agents. Many patients with advanced disease can benefit from palliative radiation, but the combination of radiation with immunotherapy has the potential to increase the toxicity of both modalities. Intriguingly, the combination also has the potential to enhance the efficacy of both modalities. For this reason, combining immunotherapy and radiation may help salvage patients with recurrent localized disease who are candidates for re-irradiation. We review the current data evaluating immunotherapy with both palliative radiation as well as definitive re-irradiation in NSCLC.

Acute pain management in radiation oncology: Quality of care and the impact of an integrated palliative oncology service.

195 Background: Radiotherapy (RT) effectively palliates bone metastases, but relief may take weeks, frequently necessitating acute pain management (APM). NCCN Guidelines for Adult Cancer Pain (V2.2015) recommend initiation/titration of analgesics for patients with pain scale value (PSV) ≥ 4. We sought to evaluate how often symptomatic patients have analgesic regimens assessed and intervened upon at radiation oncology (RO) consult for bone metastases, and the impact of a dedicated palliative RO service on APM. METHODS We reviewed consult notes for 217 bone metastases patients treated with RT at Dana Farber Cancer Institute/Brigham & Womens Hospital (DFCI/BWH) and University of California, San Francisco (UCSF) during June-July 2008, Jan-Feb 2010, Jan-Feb 2013, and June-July 2014, time periods before and after implementation in 2011 of a dedicated palliative RO service at DFCI/BWH. For symptomatic patients, rate of assessment of analgesic regimen was recorded. Among patients with PSV ≥ 4, rate of pain intervention was recorded. The impact of a palliative RO service on these rates was evaluated. RESULTS Median age was 63 and median KPS was 70. Median PSV for painful bone metastases was 5 (IQR 2-7); 51% had PSV ≥ 4. Among symptomatic patients, analgesic regimen was assessed for 44.5% (51.7% at DFCI/BWH and 28.1% at UCSF). Among patients with PSV ≥ 4, pain intervention occurred for 17.2% (20.5% for DFCI/BWH, 0% for UCSF). At DFCI/BWH, consultation by a dedicated palliative RO provider was associated with higher rate of assessment of analgesic regimen (82.4% vs 47.7%, p = 0.007). At DFCI/BWH, consultation by a palliative RO provider was associated with higher rate of pain intervention (31.2% vs 7.9%, p = 0.012). There was no difference in analgesic regimen assessment or intervention between non-dedicated palliative RO providers at DFCI/BWH and UCSF (p = 0.07 and 0.09, respectively). CONCLUSIONS At two cancer centers, half of bone metastases patients seen for RT have PSV ≥ 4, yet a minority have analgesic assessment and intervention, indicating need for APM quality improvement in RO. An integrated palliative RO service was associated with improved assessment and management of acute pain per NCCN guidelines.

Piling up the JNK Drug synergy through ER stress

Commentary to: BCL-2 antagonists interact synergistically with bortezomib in DLBCL cells in association with JNK activation and induction of ER stress Girija Dasmahapatra, Dmitry Lembersky, Mohamed Rahmani, Lora Kramer, Jonathan Friedberg, Richard I. Fisher, Paul Dent, Steven Grant

Palliative Care Specialist Series: Top 10 Tips Palliative Care Clinicians Should Know About Radiation Oncology

Abstract As palliative care (PC) moves upstream in the course of advanced illness, it is critical that PC providers have a broad understanding of curative and palliative treatments for serious diseases. Possessing a working knowledge of radiation therapy (RT), one of the three pillars of cancer care, is crucial to PC providers given RTs role in both the curative and palliative settings. This article provides PC providers with a primer on the vocabulary of RT; the team of people involved in the planning of RT; and common indications, benefits, and side effects of treatment.As palliative care (PC) moves upstream in the course of advanced illness, it is critical that PC providers have a broad understanding of curative and palliative treatments for serious diseases. Possessing a working knowledge of radiation therapy (RT), one of the three pillars of cancer care, is crucial to PC providers given RTs role in both the curative and palliative settings. This article provides PC providers with a primer on the vocabulary of RT; the team of people involved in the planning of RT; and common indications, benefits, and side effects of treatment.

Impact of a dedicated palliative radiation oncology service on the use of single fraction and hypofractionated radiation therapy among patients with bone metastases

BACKGROUND Radiation therapy (RT) is frequently used to palliate symptomatic bone metastases. While high quality literature has shown that for uncomplicated bone metastases, shorter radiotherapy courses are just as effective as longer courses for the treatment of pain, shorter courses remain under-utilized. We aimed to assess the impact of a dedicated palliative radiation oncology service on the frequency of single fraction RT (SF-RT) and hypofractionated radiation (hypo-RT) (≤5 fractions) among patients with bone metastases. METHODS We identified 2,086 instances of palliative radiation (RT) for complicated and uncomplicated bone metastases between April 10, 2008 and September 17, 2014. We used multivariable logistic regression analysis (MVA) to estimate the association of the Supportive and Palliative Radiation Oncology (SPRO) service with the likelihood of receiving SF-RT or hypo-RT after controlling for age, sex, tumor type, and treatment site. RESULTS Prior to SPROs implementation on July 1, 2011, the proportion of SF-RT and hypo-RT for bone metastases was 6.4% and 27.6% respectively. After SPROs implementation, the proportion of SF-RT and hypo-RT increased to 22.3% (P<0.001) and 53.5% (P<0.001) respectively. In MVA, patients were more likely to receive SF-RT [odds ratio (OR) =3.3, 95% confidence interval (CI) =2.4-4.7, P<0.001], and hypo-RT (OR =2.5, 95% CI =2.0-3.1, P<0.001) after SPROs implementation. Compared to sites without a dedicated palliative service, patients receiving care at the SPRO affiliated department were more likely to receive SF-RT (OR =1.9, 95% CI =1.1-3.2, P=0.02) and hypo-RT (OR =1.5, 95% CI =1.1-2.0, P=0.004) for bone metastases. After SPROs implementation, the average number of RT courses delivered for bone metastases increased from 17.4 to 25.6 per month, (+8.3, 95% CI =4.99-11.55, P<0.001). Despite greater SF-RT and hypo-RT, the average total fractions per month of palliative RT for bone metastases increased from 163.5 pre-SPRO to 166.8 post-SPRO, though not significantly (+3.22, P=NS). CONCLUSIONS Implementation of a dedicated palliative radiation oncology service was associated with increased use of SF and hypo-RT and with greater courses of RT delivered for bone metastases.